| Invited Lecture(JSGE) |
| Fri. November 1st 14:40 - 15:10 Room 4: Portopia Hotel South Wing Portopia Hall |
| Immune microenvironment in liver cancer - the importance of metabolic alterations in health and in disease | |||
| Mathias Heikenwalder | |||
| German Cancer Research Center | |||
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| The liver is the central metabolic organ of the body, regulating energy and lipid metabolism, while also having potent immunological functions. Overwhelming the metabolic capacity of the liver via obesity and a sedentary lifestyle leads to hepatic lipid accumulation, chronic necro-inflammation, enhanced mitochondrial/endoplasmic reticulum stress and development of metabolic dysfunction- associated steatotic liver disease (MASLD), and its more severe form of metabolic dysfunction-associated steatohepatitis (MASH). Moreover, other etiologies in combination with MASLD as smoking or chronic alcohol-related steatohepatitis (ASH) can contribute to chronic liver damage and liver cancer. Based on an improved understanding of pathophysiological mechanisms, specifically targeting metabolic pathways to prevent or slow down the progression of MASLD to liver cancer will become possible. Genetic/environmental factors are also known to contribute to the development of MASH and progression to liver cancer. The complex pathophysiology of MASLD-MASH is reflected by environmental factors, particularly the gut microbiome and its metabolic products. MASLD-associated HCC most often occurs in the context of a chronically inflamed and cirrhotic liver. Recognition of environmental alarmins or metabolites derived from the gut microbiota and the metabolically injured liver create a strong inflammatory milieu supported by innate and adaptive immunity. Several recent studies indicate that MASH induces auto-aggressive CD8+CXCR6+PD1+ T cells that eliminate parenchymal and non-parenchymal cells in an antigen-independent manner. This promotes chronic liver damage and a pro-tumorigenic environment. CD8+CXCR6+PD1+ T cells possess an exhausted, hyperactivated, resident phenotype; they trigger the MASH to HCC transition and might be responsible for weaker responses to immune checkpoint inhibitors - in particular atezolizumab/bevacizumab. In my presentation I will cover MASH-related inflammation/pathogenesis mechanisms, focusing on new discoveries on the role of T cells and drug-repurposing or life style alterations to treat or prevent MASH-HCC treatment. References: 1) Pfister D, ..., Llovet JM*, Heikenwalder M*. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021 Apr;592(7854):450-456. doi: 10.1038/s41586-021-03362-0. Epub 2021 Mar 24. PMID: 33762733; PMCID: PMC8046670. 2) Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021 Sep;21(9):541-557. doi: 10.1038/s41568-021-00383-9. Epub 2021 Jul 29. PMID: 34326518. 3) Gallage S, et al.,..., Heikenwalder M. A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1. Cell Metab. 2024 Jun 4;36(6):1371-1393.e7. doi: 10.1016/j.cmet.2024.04.015. Epub 2024 May 7. PMID: 38718791. |
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